The PI is a physician-scientist and gastroenterologist whose long-term career goal is to independently lead a respected, multidisciplinary research program that is keenly focused on personalizing Helicobacter pylori (H pylori) management in order to optimize disease-, treatment-, and systems-related outcomes among Veterans. This CDA-2 is designed to transform the PI into VA Merit-funded researcher with methodologic proficiency in big data analysis, genetic epidemiology, and advanced epidemiologic methods, and scientific proficiency in H pylori pathobiology. The PI is well-supported by mentors whose expertise and wealth of unique resources quintessentially bridge her career and research objectives, and by deeply supportive and collaborative institutions. The PI is committed to advancing Veteran health by providing exceptional patient care at the bedside and by conducting cutting-edge, clinically relevant science. H pylori is the strongest known risk factor for gastric cancer, a malignancy which claims over 780,000 lives annually and remains the 3rd leading cause of cancer-related mortality. This pathogen is also directly causative for other diseases with high morbidity and mortality, including peptic ulcer disease. H pylori infects approximately 28% of all Veterans, with the prevalence exceeding 50% among racial and ethnic minorities. H pylori eradication necessitates 10-14 days of 2-3 antibiotics and high-dose acid suppression. Successful eradication has led to a decreased incidence of gastric cancer and other diseases for which H pylori is causative. However, rising rates of H pylori eradication failure threaten these successes and contribute to the massive burden of antibiotic resistance and other adverse consequences, since eradication failure is managed with repeated courses of therapy. Indeed, in 2017 the World Health Organization designated H pylori eradication failure a research priority area, which speaks to its critical importance and broad health impact. The reasons underlying eradication failure are multifactorial and, apart from antibiotic resistance, have not been completely investigated. We hypothesize that defining host-level determinants of eradication failure will maximize the initial success of eradication by providing an anchoring point on which to develop a personalized approach to therapy. We further hypothesize that a personalized approach will improve individual treatment response, reduce the unintended downstream consequences of eradication failure and, consequently, improve H pylori- related outcomes among Veterans. In this proposal, the PI will leverage two powerful VA databases, the Corporate Data Warehouse (CDW) and the Million Veteran Program (MVP), the electronic health record- linked genomic biobank, to first construct a cohort of Veterans from each database who completed H pylori testing (approximately 10% of all Veterans based on preliminary data). A sub-cohort of Veterans who were treated and had post-treatment H pylori testing to assess eradication success will also be constructed from MVP specifically (~18,000 of the over 650,000 genotyped Veterans). Using these two cohorts, the PI will define the prevalence of H pylori, the frequency and type of anti-H pylori therapy, select antibiotic resistance patterns, the frequency of eradication failure as well as time trends and regional variations (AIM 1). This will be followed by defining the genetic and non-genetic determinants of H pylori eradication failure using GWAS (AIM 2), multivariable logistic regression and Mendelian randomization (AIM 3) study designs, respectively. Predictive models for antibiotic resistance based on non-invasive data will also be constructed and validated. This work is significant because it will fill critical knowledge gaps of H pylori epidemiology and treatment among Veterans. In future prospective studies as an independent VA investigator, the PI will integrate host-level determinants of eradication failure into a clinical support tool that can be translated to the bedside for personalization of H pylori eradication therapy based on individual-level factors in an effort to optimize Veteran health.